The invention is in the field of therapeutics and medicinal chemistry. More particularly, the invention concerns methods to enhance white blood cell counts in subjects by administering certain cyclic polyamines.
White blood cells play a significant part in maintaining the health and viability of animals, including humans. These white blood cells include neutrophils, macrophage, and basophils/mast cells as well the B and T cells of the immune system. White blood cells are continuously replaced (as are red blood cells and clot forming cells) by the hematopoietic system in response to a number of growth factors, such as colony stimulating factors (CSF) and various cytokines. The nucleotide sequences encoding a number of these growth factors have been cloned and sequenced. Perhaps the most widely known of these is granulocyte colony stimulating factor (G-CSF) which has been approved for use in counteracting the negative effects of chemotherapy. A discussion of the hematopoietic effects of this factor can be found, for example, in U.S. Pat. No. 5,582,823, incorporated in its entirety by reference herein.
While endogenous growth factors are pharmacologically effective, the well known disadvantages of employing proteins and peptides, as opposed to small molecules, as pharmaceuticals underlies the need to add to the repertoire of such growth factors compounds which are themselves small molecules. In another aspect, such small molecules are advantageous over proteins and peptides where production in large quantities are desired.
A number of cyclic polyamine antiviral agents have been described in a series of U.S. patents and applications over the last several years. These patents, U.S. Pat. Nos. 5,021,409; 5,583,131; 5,698,546; and 5,817,807 are incorporated herein by reference. Also incorporated by reference is copending application Ser. No. 09/111,895 filed Jul. 8, 1998, which describes additional compounds. These patents describe the structural characteristics of the cyclic polyamine antiviral agents.
In addition, improved methods for preparation of some of these compounds are described in U.S. Pat. Nos. 5,612,478; 5,756,728; 5,801,281; and 5,606,053. The disclosures of these U.S. patents are also incorporated herein by reference in their entirety.
It has now been found that the cyclic polyamine antiviral agents described in the above-mentioned patents have the effect of enhancing production of white blood cells as well as exhibiting antiviral properties. Thus, these agents are useful where treatment affects the activities within the bone marrow resulting in leukopenia, thus controlling the side-effects of chemotherapy, radiotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein.
The invention is directed to methods of treating animal subjects, in particular, veterinary and human patients, who are defective in white blood cell (WBC) count, or who would benefit from elevation of WBC levels. The methods of the invention employ cyclic polyamines including those described in the patents incorporated hereinabove by reference.
In one aspect, therefore, the invention is directed to a method to elevate the white blood cells (WBC) count, in a subject in need of such WBC elevation, which method comprises administering to said subject an amount of a compound of formula (1) or of a pharmaceutical composition thereof effective to elevate WBC levels.
In additional aspects, the invention is directed to pharmaceutical compositions containing the compound of formula (1) for use in effecting WBC count elevation in animal subject.
The compounds of formula (1) are of the formula:
Z-linker-Zxe2x80x2xe2x80x83xe2x80x83(1)
wherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms;
said nitrogen atoms separated from each other by at least 2 carbon atoms,
wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system.
Zxe2x80x2 may be embodied in a form as defined by Z above, or alternatively may be of the formula
xe2x80x94N(R)xe2x80x94(CR2)nxe2x80x94X
xe2x80x83wherein
each R is independently H or straight, branched or cyclic alkyl (1-6C),
n is 1 or 2, and
X is an aromatic ring, including heteroaromatic rings, or is a mercaptan;
xe2x80x9clinkerxe2x80x9d represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.
The preferred forms of the compounds of the invention are discussed below.